Gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH) complicate 2-3% and 5-10% of all pregnancies, respectively. These disorders can occur in the third-trimester of pregnancy and are associated with significant maternal and fetal morbidity and mortality. Gestational diabetes has been described as the new onset or new diagnosis of glucose intolerance during pregnancy and is associated with fetal complications relating to macrosomia, such as shoulder dystocia and birth trauma. In addition, GDM is associated with increased cesarean section rates and increased risk of PIH. PIH is associated with preterm labor, increased cesarean section rates, acute renal failure, hepatic dysfunction, stroke, coagulopathy, and death. For the fetus, PIH is associated with low birth weight, extended neonatal intensive care, and intrauterine death.
Prospective studies suggest chronic subclinical inflammation, whether measured in a global fashion with c-reactive protein (CRP) or with specific cytokines, is an important risk factor for type 2 diabetes mellitus. Elevated high sensitivity-CRP levels in the first trimester may be indicative of increased risk for developing GDM. Thus, inflammatory markers and measures of insulin resistance measured in blood early in gestation may be associated with subsequent development of GDM and/or PIH. While serum CRP results have been positive, measurement of inflammatory markers limits the potential understanding of the inflammatory repertoire associated with these outcomes in pregnancy. Furthermore, CRP remains a biomarker, and not a cytokine potentially involved in the pathogenesis of disease. Finally many studies are done at the time of preeclampsia and not before, so their predictive power is limited.
Individuals at increased risk of developing preeclampsia and eclampsia include primigravidas and women with multiple gestations, molar pregnancy or fetal hydrops, chronic hypertension or diabetes, or a personal or family history of eclampsia or preeclampsia. Preeclampsia (PE) and gestational hypertension (GH) are forms of PIH. Preeclampsia is generally defined as the combination of high blood pressure (hypertension), swelling (edema), and protein in the urine (albuminuria, proteinuria) developing after the 20th week of pregnancy. Preeclampsia ranges in severity from mild to severe; the mild form is sometimes called proteinuric pregnancy-induced hypertension or proteinuric gestational hypertension. Gestational (transient) hypertension is generally characterized as the acute onset of hypertension in pregnancy or the early puerperium without proteinuria or abnormal edema and resolving within 10 days after delivery. Chronic hypertension that had been latent prior to the pregnancy may also become evident during gestation. Pregnant women with latent chronic hypertension are also at increased risk for stillbirth, neonatal death, and other fetal complications, but the risk is much lower than that of women with preeclampsia or eclampsia. Women with transient or latent chronic hypertension are also more likely to develop chronic hypertension in later years.
In general, the definition of GDM provides that two or more of the following blood glucose values meet or exceed the following thresholds: fasting, 95 mg/dl (5.3 mmol/L); 1 hour 180 mg/dl (10.0 mmol/L); 2 hours, 155 mg/dl (8.6 mmol/L); 3 hours, 140 mg/dl (7.8 mol/L). Alternatively, testing can be performed in a single step using only the 75-100 gm oral glucose tolerance test (OGTT) without prior glucose screening. In either case, the definition of GDM can be based on the results of the 75-100 gm OGTT.
The present standard therapy for PIH, including PIH resulting from GDM, is delivery, often at the expense of fetal well-being. Prophylactic strategies to prevent PIH, including calcium supplementation and aspirin therapy, have been mostly unsuccessful. One reason these trials have failed is that the absence of screening tests limited the ability to administer the therapeutic interventions early enough to modify pregnancy outcome. For example, diagnosing PE by the appearance of edema and proteinuria alone is unreliable as edema is common in normal pregnancies and measurable proteinuria usually occurs only after hypertension is manifested. Therefore, such a test lacks specificity and fails to detect GDM or PIH prior to manifestation of the disease in the third trimester of pregnancy.
Currently, no single biochemical marker, or plurality of biochemical markers, reliably identifies women at risk for developing GDM or PIH prior to the third trimester of pregnancy. Thus, there exists a need for diagnostic methods and compositions that lead to early implementation of therapy and improved pregnancy outcomes for women at risk for gestational disorders.